Chemical synapses mediate the transmission of electrical signals among nerve cells (neurons) and thus serve a critical role in all aspects of neural function and neurological disease. Understanding the in vivo molecular mechanisms of synaptic transmission is a major challenge because genetic manipulation often disrupts proper development or maintenance of synaptic connections within the nervous system. The Drosophila model system offers a sophisticated approach involving use of temperature-sensitive (TS) paralytic mutants for genetic analysis of evolutionarily conserved synaptic mechanisms. These mutants can permit normal neural development and function while allowing acute perturbation of a specific gene product upon exposure to elevated temperatures. In this way, the in vivo physiological roles of specific gene products may be addressed at native synapses. The powerful genetics of Drosophila allows screens for new TS paralytic mutants affecting synaptic transmission and thus the identification and characterization of novel synaptic mechanisms. The proposed study will characterize a new TS paralytic mutant, e(cac)2902, which was isolated as an enhancer of the TS presynaptic calcium channel mutant, cacTS2. The e(cac)2902 mutant exhibits rapid paralytic and a clear TS synaptic phenotype. Like cacTS2, e(cac)2902 produces a marked reduction the excitatory postsynaptic current (EPSC) amplitude at restrictive temperatures. Genetics characterization has mapped the e(cac)2902 to a small interval of the second chromosome containing no genes previously implicated in synaptic transmission. The proposed studies will reveal the molecular identity of the e(cac)2902 gene product and characterize its role in synaptic function. These studies will broaden our understanding of the in vivo mechanisms of synaptic function and help provide a molecular basis for therapies to combat neurological disease. PUBLIC HEALTH RELEVANCE: The transmission of electrical signals among nerve cells (neurons), which is critical to all aspects of neural function and disease, occurs at structural connections between neurons called chemical synapses. The proposed studies take advantage of powerful genetic approaches available in the fruit fly, Drosophila melanogaster, to study evolutionarily conserved mechanisms of synaptic function. Characterization of a novel mutant exhibiting a temperature- dependent defect in synaptic transmission is expected to provide new insights into the in vivo molecular mechanisms of normal synaptic function and its role in neurological disease.